Molecular determinants of post-mastectomy breast cancer recurrence.

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Future cancer research priorities in the USA: a Lancet Oncology Commission.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

Serum metabolomic profiles evaluated after surgery may identify patients with oestrogen receptor negative early breast cancer at increased risk of disease recurrence. Results from a retrospective study.

PURPOSE: Metabolomics is a global study of metabolites in biological samples. In this study we explored whether serum metabolomic spectra could distinguish between early and metastatic breast cancer patients and predict disease relapse. METHODS: Serum samples were analysed from women with metastatic (n = 95) and predominantly oestrogen receptor (ER) negative early stage (n = 80) breast cancer using high resolution nuclear magnetic resonance spectroscopy. Multivariate statistics and a Random Forest classifier were used to create a prognostic model for disease relapse in early patients. RESULTS: In the early breast cancer training set (n = 40), metabolomics correctly distinguished between early and metastatic disease in 83.7% of cases. A prognostic risk model predicted relapse with 90% sensitivity (95% CI 74.9-94.8%), 67% specificity (95% CI 63.0-73.4%) and 73% predictive accuracy (95% CI 70.6-74.8%). These results were reproduced in an independent early breast cancer set (n = 40), with 82% sensitivity, 72% specificity and 75% predictive accuracy. Disease relapse was associated with significantly lower levels of histidine (p = 0.0003) and higher levels of glucose (p = 0.01), and lipids (p = 0.0003), compared with patients with no relapse. CONCLUSIONS: The performance of a serum metabolomic prognostic model for disease relapse in individuals with ER-negative early stage breast cancer is promising. A confirmation study is ongoing to better define the potential of metabolomics as a host and tumour-derived prognostic tool.

Surgical patterns of care in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast magnetic resonance imaging: results of a secondary analysis of TBCRC 017.

BACKGROUND: Neoadjuvant chemotherapy (NCT) downstages advanced primary tumors, with magnetic resonance imaging (MRI) being the most sensitive imaging predictor of response. However, the impact of MRI evaluation on surgical treatment decisions in the neoadjuvant setting has not been well described. We report surgical patterns of care across 8 National Cancer Institute comprehensive cancer centers in women receiving both NCT and MRI to evaluate the impact of MRI findings on surgical planning. METHODS: Seven hundred seventy women from 8 institutions received NCT with MRI obtained both before and after systemic treatment. Univariate and multivariate analyses of imaging, patient-, and tumor-related covariates associated with choice of breast surgery were conducted. RESULTS: MRI and surgical data were available on 759 of 770 patients. A total of 345 of 759 (45 %) patients received breast-conserving surgery and 414 of 759 (55 %) received mastectomy. Mastectomy occurred more commonly in patients with incomplete MRI response versus complete (58 vs. 43 %) (p = 0.0003). On multivariate analysis, positive estrogen receptor status (p = 0.02), incomplete MRI response (p = 0.0003), higher baseline T classification (p < 0.0001), younger age (p < 0.0006), and institution (p = 0.003) were independent predictors of mastectomy. A statistically significant trend toward increasing use of mastectomy with increasing T stage at presentation (p < 0.0001) was observed in patients with incomplete response by MRI only. Among women with complete response on MRI, 43 % underwent mastectomy. CONCLUSIONS: Within a multi-institutional cohort of women undergoing neoadjuvant treatment for breast cancer, MRI findings were not clearly associated with extent of surgery. This study shows that receptor status, T stage at diagnosis, young age, and treating institution are more significant determinants of surgical treatment choice than MRI response data.

Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657.

PURPOSE: Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers. PATIENTS AND METHODS: Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets. RESULTS: In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets. CONCLUSION: In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.